Synthesis of 2-amino-3-methoxy 5-chloro pyrazine



United States Patent cc 3,158,612 SYNTHESIS 0F Z'ARQING3ERIETI'EGXY S-CHLQRQ PYRAZENE Luigi Blernardi, Milan, and Giovanni Larini and Ansehno Leone, Settirno Torinese, Turin, Etaly, assignors to Societa Farrnaceutici ltalia, Milan, Italy, a corporation of Italy No Drawing. Griginal application Nov. 3, 1'96 Ser. No. 149,852. Divided and this application fiept. 17, 1962, Ser. No. 230,023

Claims priority, app!ieation Italy, Nov. '7, 1966, 19,2-34/66 1 shim. (uuzoufim The processof the present nvention follows the following scneme:

SCHEME HtN sorotni-Nnz NHS moat-N112 or -o1 III NH: (3H2 EtO o o o 0 Et 0 0 0 NH N N N V z =0 Chlorine NH S O2 aH4+NH H2 I INHSOZQEH4 NHQ Alk-oNfl o =0 01 Cl 01 -oorr, 0orr,

NH N 1 II IV 1 ClSO o H NHA Nnion F 3 4 c (2) Hydrolysis NH2 OH ONa C1 -01 Cl 0 0 H3 VI VII This application is a division of our U.S. patent application Serial No. 149,852, filed November 3, 1961.

The invention relates to a number of new pyrazine derivatives .and to a process of preparing them. It particularly relates to a new process for obtaining the sulfa drug 3-methoXy-2-sulfapyrazine, employing therein novel derivatives of 2,3-bis-substituted 5-chloro-pyrazine having the following general formula:

Cl R2 3,158,612 Patented Nov. 24, 1964 cause the yields are low, and/or long and expensive operations are required to obtain the said intermediates.

Our search for new and economical methods of synthesis of the S-methoXy-ZeuIfapyraZine resulted in an advantageous and unexpected process for the preparation of the above said su'lfonarnide, through the said novel pyrazine derivatives. Also, a number of said novel pyrazine derivatives are useful both for their bacterio static properties as well as their'utility as intermediates for the production of other pyra zines useful invarious fields.

The starting product for the process, of the present invention is 2,3,5-triketo-piperazine (I), a substance hitherto obtainable by the complex synthesis described by M. Bergman et al. in the Ztsch. fiir 'l hysiol. C hein. 146, 1925, page 247. 1

In accordance with the present invention, the 2,3,5- triketo-piperazine is conveniently and advantageously synthesized by condensing amino-acetamide (prepared as described by GcKarmas and P. Spoerri in I. AnnChern. Soc. 74, 1952, page 1580) or one of itssalts with a mineral acid, such as the hydrochloride, with ethyl oxalate either in solution or in suspension in loweraliphat-ic alcohols preferably methanol or ethanol, in the presence of the sodium, salt of the alcohol (1 mole if the free base of amino-acetmide is used or 2 lnoles ifthe hydrochloride of amino-acetamide is used), over aperiod of time ranging from 15 minutes to several hours at 49-80 C., preferably at the boiling temperature of the reaction mixture. The yield of 2,3,5-triketo-piperazine is almost quantitative.

The 2,3,5-triketo-piperazine is then chlorinated to 2,3, S-trichloro-pyrazine (II) by reaction With phosphorus oxychloride or a mixture of phosphorus oxychloride and phosphorus pentachloride, preferably or optionally in the presence of tertiary amines such as pyridine or dimethylaniline, preferably at a temperature between and C. over a period of tirneranging from several hours to 100 hours, preferably from 2 to 60 hours.

5-chloro-3-rnethoxy-Z-sulfapyrazine (IV) is prepared from the 2,3,5-trichloro-pyrazine (II) through either of two syntheses.

In one synthesis, 2,3,S-trichloro-pyrazine (II) is transformed into 3,5-dichloro-2-sulfapyrazine (III), by reaction with sulfanilarnide in the presence of an acid acceptor such as potassium carbonate or acetate or an allraline salt of sulfanilamide, at a temperature ranging from 80 to 150 C., in the presence or not of high boiling solvents. Upon treating the 3,S-dichloro-Z-sulfapyrazine with an alkaline salt of methyl alcohol in alcoholic solution, such as sodium or potassium methylate in methyl alchol at 40-120 C. for 2-20 hours, -chloro-3-methoxy- 2-sulfapyrazine (IV) is obtained.

In the other synthesis, 2,3,S-trichloro-pyrazine (II) is first transformed into 2-arnino-3,S-dichloro-pyrazine (VI) by reaction with aqueous ammonia, preferably at 69- 140 C. under pressure for 6-30 hours. Upon treatment of (VI) with an alkaline salt of methyl alcohol in alcoholic solution, such as the sodium or the potassium methylate in methyl alcohol, at 40-120 C. for 2-20 hours, 2-amino-5-chloro-3-methoxy-pyrazine (VII) is obtained. Upon condensation of (VII) with a para-acylaminobenzene-sulfohalide, such as the para-acetylaminobenzene-sulfochloride, in the presence of a tertiary amine, such as pyridine, mixed or not with acetone, and thereafter saponifying, with alkali, the acetyl linkage in the N position of the sulfonilamidic group, (VIII) is transformed into the 5-chloro-3-methoxy-2-sulfapyrazine (IV).

Finally the product (IV), by hydrogenation, preferably at room temperature and atmospheric pressure, in the presence of a catalyst such as 5l0% palladium over charcoal, and of an acid acceptor, such as the sodium hydroxide or the potassium hydroxide, or triethylamine, or other tertiary amine, is transformed into the 3-methoxy- 2-sulfapyrazine (V).

The success of the processes of the present invention, for preparing the 3-methoxy-2-sulfapyrazine, is based upon the discovery that 2,3,5-trichloro-pyrazine (II) reacts selectively in the 2-position, in the conversion with ammonia to compound (VI), as well as in the alternative conversion with sulfanilamide to compound (III). It was quite unexpected that the treatment of the 2,3,5-trichloro-pyrazine with sulfanilamide or ammonia should only, or prevalently, cause the substitution of the chloro atom in the 2-position of the pyrazine ring by a sulfanilyl or amino radical respectively. Also, the selective methoxylations in the 3-position of 2-sulfanilamido-3,S-dichloropyrazine, and of 2-amino-3,S-dichloropyrazine, are unexpected reactions. These reactions, and the subsequent substitution of the chloro atom With hydrogen (the IV- V reaction), could theoretically result in three end products, namely the isomers 3-methoxy-2-sulfapyrazine (V), 5methoxy-2-sulfapyrazine, and 5-methoxy-3-sulfapyrazine (or 6-methoxy-2-sulfapyrazine). In contrast, we

have found that only one of said isomers is obtained, and

in a very good yield, namely 3-methoxy-2-sulfapyra zine (V).

Some of the novel products of the present invention,

I particularly the 3,5-dichloro-2-sulfapyrazine (III) and the 5-chloro-3-methoxy-2-sulfapyrazine (IV), have good bac teriostatic activity on infections caused by staphylococcus or streptococcus or pneumococcus or other microbial agents.

The following examples are meant to illustrate the invention Without limiting it.

EXAMPLE 1 2,3,5-Triketo-Piperazinc (I) To a boiling mixture of 13 grams of aminoacetamide, 26 grams of ethyl oxalate and 250 cm. of ethanol are added, over a period of minutes, a solution of 4.6

rams of sodium dissolved in 200 cm. of ethanol. The reaction mixture is kept at boiling temperature for a further 30 minutes, is then cooled and the sodium salt of the triketo-piperazine is filtered ott, in quantitative yield. The free triketo-piperazine base is obtained by dissolving the sodium salt in 2 N HCl, or by suspending the salt in an inert solvent saturated with HCl. In the latter case, the separated triketo-piperazine contains NaCl as impurity but can be employed in the succeeding chlorination.

In the same manner, aminoacetamide hydrochloride is condensed with ethyl oxalate in methanol, in the presence of two moles of sodium methylate. The sodium salt of triketo-piperazine which separates contains NaCl as impurity but can be employed in the succeeding chlorination.

EXAMPLE 2 2,3,5-Trichloro-Pyrazine (II) From I (Method With POCZ and PCl Into a Carius tube are poured 1 gram of 2,3,5-triketopiperazine (I), 3 cm. of phosphorus oxychloride, and 6 grams of phosphorus pentachloride. The mixture is heated to 110 C. for 60 hours. Then it is cooled, poured into ice, extracted with dichloromethane, and the solvent then evaporated. 0.8 gram of 2,3,5-trichloro-pyrazine are obtained: It is a white product melting at about 32 C.

EXAMPLE 3 2,3,5-Ti'ichloro-Pyrazine (II) From 1 (Method With the POCI Alone) Into a Carius tube are poured 1 gram of 2,3,5-triketopiperazine (I), 8 cm. of phosphorus oxychloride, and 1 gram of dimethylaniline. The mixture is heated to 150 C. for 4 hours, cooled, poured into ice, extracted with dichloromethane, and the solvent evaporated. 0.6 gram of 2,3,5-trichloropyrazine are obtained: It is a White product melting at about 32 C.

EXAMPLE 4 3,5-Dz'chl0r0-2-Sulfapyrazine (III) From II 27 grams of 2,3,5-trichloro-pyrazine (II) are added to 60 grams of sodium sulfanilamide in 60 grams of acetamide. The mixture is heated to 100 C. for 1 hour. The solution is filtered, acidified with acetic acid and the 3,5-dichloro-Z-sulfapyrazine which separates is filtered. Yield: melting point:l79l80 C.

Pure 3,5-dichloro-Z-sulfapyrazine is crystallized from Cellosolve. Its melting point is 188491 C.

EXAMPLE 5 2-Amino-j,S-Diclzloro-Pyrazine (VI) From ll 2,3,5-trichloro-pyrazine (II) is reacted with concentrated aqueous ammonia at C. for 3 hours. The 2- amino-3,S-dichloro-pyrazine is then isolated. Yield: 80%; melting point=l40142 C.

EXAMPLE 6 5-Chlore-3Jilethoxy-Z-Su[fapyrazine (IV) From 111 14 grams of crude 3,5-dichloro-2-sulfapyrazine (III) are added to a solution of 3 grams of sodium in 200 cm. of methanol, and heated in an autoclave for 15 hours to 115 C. It is then cooled, the methanol evaporated, the mixture diluted with Water, and acidified with acetic acid. Crude 5-chloro-3-methoxy-2-sulfapyrazine separates from the solution and is filtered oil. Yield: 80%; melting point=l76-l79 C.

Pure 5-chloro-3-methoxy-2-sulfapyrazine melts at 182 C. (crystallized from Cellosolve).

EXAMPLE 7 2-Amino-5-Chl0ro-3-Methoxy-Pyrazine (VII) From Vl To a solution of 21 grams of sodium in 50 cm. of methanol 11 grams of 2-amino-3,S-dichloro-pyrazine (VI) are added. The mixture is refluxed 4 hours; the methanol is eliminated, and the residue is pulped with water and the product filtered off. Yield of (VII): 90%; melting point:110-113 C.

A sample crystallized from benzene-petrol ether melts at 128l31 C.

EXAMPLE 8 5-Chl0ro-3-Methoxy-2-Sulfapyrazine (IV) From VII The 2-amino-5-chloro-3-methoxy-pyrazine (VII) dissolved in pyridine is mixed with p-acetylamino-benzenesulfochloride, at a cool temperature and under stirring. The reaction mixture is kept for hours at room temperature, and is then heated to C. for 4 hours. The solution is concentrated in vacuo to about one third of its volume, and is then poured into ice-water.

The product is filtered and Washed with water. The 2 (p acetylamino-benzene-sulfonamido) 5 chloro 3- rnethoxy-pyrazine thus obtained is de-acetylated by refluxing with 10% aqueous NaOH for 1 hour.

The solution is then cooled, and is slightly acidified (pl-i=6) with 2 N HCl. The 5-chloro-3-methoxy-2-sulfapyrazine is thus isolated. Yield: melting point: ISO-182 C.

EXAMPLE 9 3-Methoxy-Z-Sulfapyrazine (V) From IV To 8 grams of 5-chloro-3-methoxy-2-sulfapyrazine (IV), dissolved in cm. of Water containing 3 grams of sodium hydroxide, are added 4 grams of 5% palladium over charcoal and hydrogenated under atmospheric pressure. When absorption of hydrogen is over, the catalyst is filtered 01? and the filtrate acidified with acetic acid. Crude 3-methoxy-2-sulfapyrazine separates. It melts at 164-166 C. (Yield: 85%).

Pure 3-methoxy-2-sulfapyrazine, crystallized from ethyl- Cellosolve-water, melts at C.

The reaction sequence employed to make 2-amino-3- methoxy-S-chloro-pyrazine is based on the unexpected property of 2,3,5-trichloro-pyrazine of reacting selectively in the 2-position, in the conversion With aqueous ammonia to give 2-amino-3,S-dichloro-pyrazine (VI). It was unexpected that by reacting 2,3,5-trichloro-pyrazine with aqueous ammonia only the Z-chloro-atom is replaced by an amino-group, While the two chloro-atoms in the 3- and 5-position remain unaffected.

Also, the selective methoxylation in the 3-position of 2- amino-3,S-dichloro-pyrazine is an unexpected and surprising reaction. A chemist trained in heterocyclic field would have predicted the formation of several end products upon reaction of 2,3,5-trichloro-pyrazine with aqueous ammonia and subsequent reaction with sodium or potassium methylate. Among such conceivable end products are L methoxy-3-amino-S-chloro-pyrazine, 2 amino-3-chloro-5- methoxy-pyrazine, and 2-amino-3-methoxy-5-chloro-pyrazine. The prospect, and even probability, of obtaining a mixture of isomeric end products would have discouraged chemists, and have caused them to direct their efforts to other routes for preparation of 3-methoxy-2aminopyrazine.

The preparation of 3-methoxy-2-amino-pyrazine from 2,3,5-trichloro-pyrazine constitutes a reduction to practice or" a process which, in advance, on paper, had not the slightest probability of success.

We claim:

A process for preparing Z-amino-3-methoxy-5-chloropyrazine which comprises reacting 2,3,5-trichloro-pyrazine with aqueous ammonia, to make 2-amino-3,5-dichloro-pyrazine, and reacting said product with sodium methylate in methanol to make 2-amino-3-methoxy-5- chloro-pyrazine.

References Cited in the file of this patent UNITED STATES PATENTS 2,396,067 Winnek et al Mar. 5, 1946 2,494,524 Sprague Jan. 10, 1950 3,098,069 Catnerino et al July 16, 1963 OTHER REFERENCES Elderfield: vol. 6 (1937), pages 390-1. Safir et al.: J. Org. Chem., vol. 18' (1953), pages 106 114. 

